Zampanolide, a potent new microtubule-stabilizing agent, covalently reacts with the taxane luminal site in tubulin α,β-heterodimers and microtubules

Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to β-tubulin at residues N2...

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Detalles Bibliográficos
Autores: Field, Jessica J, Pera, Benet, Calvo, Enrique, Canales, Angeles, Zurwerra, Didier, Trigili, Chiara, Rodríguez-Salarichs, Javier, Matesanz, Ruth, Kanakkanthara, Arun, Wakefield, St John, Singh, A Jonathan, Jiménez-Barbero, Jesús, Northcote, Peter, Miller, John H, Lopez, Juan Antonio, Hamel, Ernest, Barasoain, Isabel, Altmann, Karl-Heinz, Díaz, José Fernando
Tipo de recurso: artículo
Fecha de publicación:2012
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7555
Acceso en línea:http://hdl.handle.net/20.500.12105/7555
Access Level:acceso abierto
Palabra clave:Antineoplastic Agents
Binding Sites
Bridged-Ring Compounds
Cell Proliferation
Dimerization
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Kinetics
Macrolides
Magnetic Resonance Spectroscopy
Microtubules
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Taxoids
Tubulin
Tumor Cells, Cultured
Descripción
Sumario:Zampanolide and its less active analog dactylolide compete with paclitaxel for binding to microtubules and represent a new class of microtubule-stabilizing agent (MSA). Mass spectrometry demonstrated that the mechanism of action of both compounds involved covalent binding to β-tubulin at residues N228 and H229 in the taxane site of the microtubule. Alkylation of N228 and H229 was also detected in α,β-tubulin dimers. However, unlike cyclostreptin, the other known MSA that alkylates β-tubulin, zampanolide was a strong MSA. Modeling the structure of the adducts, using the NMR-derived dactylolide conformation, indicated that the stabilizing activity of zampanolide is likely due to interactions with the M-loop. Our results strongly support the existence of the luminal taxane site of microtubules in tubulin dimers and suggest that microtubule nucleation induction by MSAs may proceed through an allosteric mechanism.

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